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Review
. 2022 Jun;66(4):546-559.
doi: 10.1111/1754-9485.13413. Epub 2022 Apr 23.

Impact of DNA damage response defects in cancer cells on response to immunotherapy and radiotherapy

Daniel Czajkowski  1 , Radosław Szmyd  2   3 , Harriet E Gee  1   2   3
Affiliations
Review

Impact of DNA damage response defects in cancer cells on response to immunotherapy and radiotherapy

Daniel Czajkowski et al. J Med Imaging Radiat Oncol. 2022 Jun.

Abstract

The DNA damage response (DDR) is a complex set of downstream pathways triggered in response to DNA damage to maintain genomic stability. Many tumours exhibit mutations which inactivate components of the DDR, making them prone to the accumulation of DNA defects. These can both facilitate the development of tumours and provide potential targets for novel therapeutic interventions. The inhibition of the DDR has been shown to induce radiosensitivity in certain cancers, rendering them susceptible to treatment with radiotherapy and improving the therapeutic window. Moreover, DDR defects are a strong predictor of patient response to immune checkpoint inhibition (ICI). The ability to target the DDR selectively has the potential to expand the tumour neoantigen repertoire, thus increasing tumour immunogenicity and facilitating a CD8+ T and NK cell response against cancer cells. Combinatorial approaches, which seek to integrate DDR inhibition with radiotherapy and immunotherapy, have shown promise in early trials. Further studies are necessary to understand these synergies and establish reliable biomarkers.

Keywords: DNA damage response; cancer; double-strand breaks; immunotherapy; radiotherapy.

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Figures

Fig. 1
Fig. 1
DSB repair pathways. Choice of the pathway is initially determined by 53BP1 and BRCA1, with 53BP1 promoting NHEJ and BRCA1 stimulating HR. NHEJ begins with Ku70‐Ku80 heterodimer binding to the broken DNA ends, followed by trimming via endonuclease Artemis and final ligation step via the LIG4‐XRCC4‐XLF‐PAXX complex. In MMEJ (sometimes also known as aEJ or TMEJ), PARP1 promotes DNA end synapsis and POLθ recruitment. After annealing of the microhomologous sequences (2–20 base pairs), the XPF/ERCC1 complex removes the redundant 3′ flaps. Subsequent ligation is mediated by LIG3/XRCC1. HR is initiated by DSB sensing by the MRN complex. Facilitated by BRCA1 and CtIP, MRN performs a short‐range resection, followed by a more extensive resection by EXO1 and/or BLM with DNA2 nuclease with subsequent coating of the 3’ ssDNA overhangs by RPA. BRCA1‐PALB2‐BRCA2 complex promotes RAD51 filament assembly. At this point, the DNA can be extended in a template‐dependent manner via SDSA, which results in a non‐crossover gene conversion. Alternatively, the formation of the double Holliday junction can resolve either as a crossover or as a non‐crossover. In contrast to MMEJ, SSA requires long regions of homology (20–25 base pairs) between the resected DNA ends. Annealing of the complementary ssDNA is mediated by RAD52, while non‐homologous flaps are digested by the XPF/ERCC1 complex. DSB, double‐strand break; 53BP1, p53 binding protein 1; BRCA1/2, breast cancer gene 1/2; NHEJ, non‐homologous end joining; HR, homologous recombination; LIG3/4, ligase 3/4; XRCC1/4, Xray repair cross‐complementing protein 1/4; XLF ‐ X‐ray repair cross‐complementing protein‐like factor; PAXX, paralogue of X‐ray repair cross‐complementing protein and X‐ray repair cross‐complementing protein‐like factor; MMEJ, microhomology‐mediated end joining; aEJ, alternative end joining; TMEJ, theta‐mediated end joining; PARP1, poly(ADP‐ribose) polymerase 1; POLθ, polymerase θ; XPF, xeroderma pigmentosum complementation group F; ERCC1 ‐ excision repair cross‐complementation group 1; DSB, double‐stranded break; MRN, meiotic recombination 11: radiation sensitive 50: Nijmegen breakage syndrome 1; CtIP, C‐terminal interacting protein; EXO1, exonuclease 1; BLM, Bloom syndrome helicase; DNA2, DNA replication helicase/nuclease 2; ssDNA, single‐stranded DNA; RPA, replication protein A; PALB2, partner and localiser of BRCA2; RAD51/52, radiation sensitive 51/52; SDSA, synthesis‐dependent strand annealing. [Colour figure can be viewed at wileyonlinelibrary.com]
Fig. 2
Fig. 2
DSB repair throughout the cell cycle. NHEJ is active in all phases of the cell cycle. In contrast, the HR pathway, which requires the presence of a homologous template for strand synthesis, takes place in the late S/G2 phase. MMEJ repair is active from early S phase until mid‐late mitosis (anaphase). However, under normal conditions, its activity is delayed until mitotic onset due to inhibitory effect of BRCA2 and RAD52. SSA is active in both early mitosis and S/G2 phase. DSB, double‐strand break; NHEJ, non‐homologous end joining; HR, homologous recombination; MMEJ, microhomology‐mediated end joining; BRCA2, breast cancer gene 2; RAD52, radiation sensitive 52; SSA, single‐strand annealing. [Colour figure can be viewed at wileyonlinelibrary.com]
Fig. 3
Fig. 3
RT induces MOMP, which triggers activation of Caspase 9‐mediated intrinsic apoptosis. If the intrinsic apoptosis is inhibited, MOMP results in release of mtDNA into a cytosol. RT also directly damages DNA leading to accumulation of cytoplasmic DNA fragments. Moreover, incorrect damage repair, drives the formation of micronuclei. mtDNA, cytoplasmic DNA and micronuclei are recognized by cGAS, which stimulates production of type‐1 IFNs in a STING‐IRF3‐dependent manner. Additionally, cytoplasmic DNA fragments can be transcribed into RNAs by the RNA polymerase III. Through activation of RIG‐I/MDA5‐MAVS‐IRF3 pathway cytoplasmic RNA species can also promote IFN‐1 signalling. Subsequent release of pro‐inflammatory cytokines and chemokines triggers Caspase 8‐mediated extrinsic apoptosis, and anti‐tumour immunity by CD8+ T and NK cells. Importantly, the anti‐tumour immunity is directed against distal lesions as well as the irradiated site in a process called the abscopal effect. RT, radiotherapy; MOMP, mitochondrial outer membrane permeabilisation; mtDNA, mitochondrial DNA; cGAS, cyclic GMP–AMP synthase; IFN, interferon; STING, stimulator of interferon genes; IRF3, interferon regulatory factor 3; RIG‐I/MDA5‐MAVS, retinoic acid‐inducible gene I/melanoma differentiation‐associated gene 5‐mitochondrial antiviral‐signalling protein. [Colour figure can be viewed at wileyonlinelibrary.com]
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